The human coronavirus-SARS (SARS-CoV) is most likely the sole agent of Severe Acute Respiratory Syndrome (SARS). Given the significant morbidity and mortality caused by SARS-CoV infections, it is important that we understand the pathogenesis of this infection, in order to design effective vaccines and antiviral therapy. Coronaviruses, particularly murine coronaviruses, have been extensively studied in the past 20 years. In this PPG, several investigators with extensive experience in the pathogenesis and molecular biology of, and host immune response to, coronaviruses and other infections will investigate the pathogenesis of SARS-CoV. The central objective will be to characterize the interaction of SARS-CoV with the immune system and with target cells in the respiratory tract. This objective will be investigated in the following projects. Project 1-To develop a murine model of SARS-CoV using recombinant SARS-CoV and HCoV-OC43, a coronavirus that causes the common cold. To examine SARS-CoV proteins for their ability to modulate the immune response in the context of coronavirus infections. Project 2-To determine if SARS-CoV proteins modulate the adaptive immune response, dendritic cell function or lung pathology, using well characterized infectious models of respiratory viral infections. To begin to identify CD8 T cell epitopes recognized in humans infected with SARSCoV using HLA-A-2 transgenic mice. Project 3-To study interactions of SARS-CoV with airway epithelia using well differentiated cultures of human airway epithelia. To investigate the role of siRNA in modifying the airway cell infection caused by SARS-CoV. Project 4-To study interactions of the surface glycoprotein, responsible for binding to susceptible cells, with its host cell receptor, with particular reference to human airway cells. To identify domains of the SARS-CoV S protein that are critical in pathogenesis. These projects are all interrelated, will provide new information about the SARS-CoV pathogenesis and will take advantage of the unique skills and expertise of the project directors and co-directors.